Treatment of MERS-CoV: Information for Clinicians Clinical decision-making support for treatment of MERS-CoV patients

16 August 2017 v4.0 About Public Health England

Public Health England exists to protect and improve the nation’s health and wellbeing, and reduce health inequalities. We do this through world-class science, knowledge and intelligence, advocacy, partnerships and the delivery of specialist public health services. We are an executive agency of the Department of Health, and are a distinct delivery organisation with operational autonomy to advise and support government, local authorities and the NHS in a professionally independent manner.

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Prepared by: Colin Brown & Antonia Scobie For queries relating to this document, please contact: colin.brown@phe.gov.uk

© Crown copyright 2017 You may re-use this information (excluding logos) free of charge in any format or medium, under the terms of the Open Government Licence v3.0. To view this licence, visit OGL or email psi@nationalarchives.gsi.gov.uk. Where we have identified any third party copyright information you will need to obtain permission from the copyright holders concerned.

Published August 2017 PHE publications gateway number: 2017180 PHE supports the UN Sustainable Development Goals Contents

About Public Health England 1

1. Document Scope 4
2. Literature 4
3. SARS-CoV Approximation of MERS 5
4. Evidence Base 5
5. Management of Cases 6 Table 1: Benefit is likely to exceed risk 8 Table 1: Data is inadequate for assessment 10 Table 1: Risk is likely to exceed benefit 11 Feedback 14 Useful Links 14 Document Authors 14 Consultation 15 Bibliography: Articles of Interest 16 1 Document scope

This evolving document is intended to provide an overview of available evidence and experience on investigational therapeutics for UK clinicians treating confirmed cases of MERS.

It was produced by PHE and the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) for the use of UK clinicians.

It is informed by literature concerning SARS, pandemic 2009 H1N1 influenza and MERS, as well discussions with international experts convened through ISARIC.

2 Literature

This document takes much of the SARS information from the following systematic review of SARS treatment: Stockman LJ, Bellamy R, Garner P, SARS: Systematic review of treatment effects, published in PLoS Med (2006;3(9):e343). A further useful review of SARS is: Cheng VCC et al, Clinical management and infection control of SARS: lessons learned, published in Antiviral Research (2013;100:407-419).

Several useful summaries of MERS treatment options have now been published: Momattin H et al, Therapeutic Options for MERS-CoV – possible lessons from a systematic review of SARS-CoV therapy, published in the International Journal of Infectious Diseases (2013;17:e792–e798), Chan JFW et al, Middle East Respiratory Syndrome Coronavirus: Another Zoonotic Betacoronavirus Causing SARS-Like Disease, published in Clinical Microbiology Reviews (2015;28(2):465-521), Arabi YM et al. Middle East Respiratory Syndrome published in New England Journal Of Medicine (2017 376(6):584-594); Colleagues with experience of managing MERS patients in affected countries have also reviewed treatment options for MERS-CoV (see Section 10 Bibliography - general).

A list of references used in this analysis is given at the end of this document. Regular literature reviews have been performed to ensure that evolving evidence is captured, up to date as of February 2017 using the search strategy detailed in Momattin et al (2013) searching across Pubmed, Embase, Scopus and the Web of Science.

A further manual review of all recent MERS-related papers in Pubmed was performed for each therapeutic option. Some information contained herein is unpublished in vitro and animal model work on MERS-CoV from several international groups to whom we are indebted. The experts consulted are listed in Section 9 - Consultation. 3 SARS-CoV approximation of MERS-CoV

Although we draw inferences from SARS in this document, there are important differences between SARS and MERS coronaviruses (CoVs), and some areas in which MERS-CoV data is not yet sufficient to enable comparison. MERS- and SARS-CoV infections demonstrate some differences in in vitro virological and immunological characteristics but the clinical relevance of these are unknown.

The limited evidence available on viral dynamics and clinical course suggest that MERS patients have shorter time from illness onset to presentation for care and requirement for ventilatory support (median seven days; range 3-11) than SARS patients, as well as associated higher respiratory tract viral loads during the first week of the illness. Some therapeutic options that showed possible clinical effects in observational human trials of SARS patients have not demonstrated in vitro inhibition of MERS-CoV.

4 Evidence base

Therapies that are plausible and supported by reasonable in vitro, animal and/or clinical data from MERS-CoV or other respiratory virus infections are shown in Tables 1, 2 and 3. A large number of other compounds have been evaluated for in vitro inhibition of MERS-CoV replication, and some have demonstrated an inhibitory effect at serum concentrations that might be achieved in patients. However, without animal studies or well-documented experience of clinical use in comparable contexts, these are not currently ready for clinical use in MERS-patients. Such therapies have therefore not been included.

There has been no significant change in recommendations of therapeutic agents since the last published version (v3.0) in September 2015 based on available evidence. Research continues to progress on the rapid development and testing of monoclonal and polyclonal human neutralizing antibodies in small animal models. These may be options for compassionate use and a phase 1 trial of a polyclonal antibody has been undertaken in healthy volunteers. Of note, one RCT testing the combination of recombinant interferon-beta1a and ritonavir-boosted lopinavir has been initiated in MERS patients in KSA (NCT02845843).

Treatment with specific therapeutic agents should ideally occur in the context of formal observational studies or controlled intervention trials (see https://isaric.tghn.org/articles/adapted-study-documents-protocols/ for open access protocols). We strongly encourage the enrollment of all patients infected with MERS-CoV into available clinical trials or observational studies on host response and viral kinetics. 5 Management of cases

5.1 Infection control

Effective infection control is essential to protect staff and patients. Instigate measures as described in the PHE guidelines: (https://www.gov.uk/government/publications/merscov-infection-control-for-possible-or-confirmed-cases) and WHO guidelines: http://who.int/csr/disease/coronavirus_infections/technical-guidance-infection/en/

5.2 Routine investigations

PHE will advise clinicians on samples for clinical and infection prevention and control purposes. (MERS clinical management and guidance is available at: https://www.gov.uk/government/collections/middle-east-respiratory-syndrome-coronavirus-mers-cov-clinical-management-and-guidance.

We recommend that initial sampling from confirmed positive cases includes blood for viral load monitoring, since this may have prognostic value, and possibly serial lower respiratory tract sampling in severe cases for monitoring response to therapy and the emergence of possible antiviral resistance. Viral sampling for research purposes could include serial upper and lower respiratory tract, blood, stool and urine samples for monitoring of viral load and persistence within body compartments. MERS-CoV titres in respiratory secretions peak during the second week of illness onset; throat swabs may be an alternative source of diagnostic samples, especially when sputum cannot be obtained.

For organisations considering studies, ISARIC has developed a generic biological sampling protocol (www.prognosis.org/isaric) and case report forms (www.prognosis.org/isaric/crf.php) which are intended to make it as easy as possible for investigators to conduct internationally-compatible research studies in an outbreak. These are available for use without restriction.

5.3 Approach to treatment

The most important recommendation remains that high-quality supportive care is the keystone of management, as expressed in the updated WHO Interim Guidance on MERS: http://www.who.int/csr/disease/coronavirus_infections/case-management-ipc/en.

The Surviving Sepsis Campaign guidelines also offer standards of care for the critically ill: http://www.survivingsepsis.org/guidelines/Pages/default.aspx

Any additional benefit of investigational pharmacological agents is uncertain, because of lack of evidence, rather than lack of plausibility. Treatment with specific therapeutic agents should ideally occur in the context of formal observational studies or controlled intervention trials (see Information for Clinicians. Clinical decision-making support for treatment of MERS-CoV patients.

https://isaric.tghn.org/articles/adapted-study-documents-protocols/ for open access protocols).

In the UK, two centres have experience of managing severely ill patients with MERS. Consultation with staff in these centres may be helpful. PHE will facilitate communications if required. WHO can also facilitate consultation with MERS experienced physicians outside of the UK.

5.4 Specific therapies

Based on the evidence presented in Table 1, convalescent plasma containing MERS-CoV antibodies, or interferon and lopinavir may be considered for specific treatment of MERS patients. Interferon and lopinavir are likely to be the most accessible treatments initially. PHE will advise on the availability of convalescent plasma once a case is identified. Specific MERS-CoV monoclonal and polyclonal antibodies are in pre-clinical development at the time of writing and a phase 1 trial of SAB-301 has been initiated in USA. UK physicians should contact PHE (Professor Maria Zambon’s office, + 44 20 8327 6810) for information about the current availability of monoclonal or polyclonal antibodies.

Other agents described in Tables 1, 2 and 3 have demonstrated antiviral effects in vitro, but without documented in vivo efficacy or sufficient clinical data, particularly in MERS patients. Some are associated with concerns about safety in clinical practice. Many require safety studies, animal studies, or both before clinical trials can be initiated. Expert consensus is to avoid those agents classified as “red”, ie corticosteroids for specific treatment of MERS, ribavirin monotherapy, and mycophenolate mofetil (MMF). In some patients corticosteroids may be considered for other indications according to local policy, for example, exacerbations of asthma/COPD, suspected or documented adrenal insufficiency or refractory septic shock (in line with the WHO Interim Guidance on MERS and Surviving Sepsis International Guidelines).

We have included promising novel antiviral agents for which compassionate use may be possible. A summary of additional MERS-CoV therapeutic candidates undergoing evaluation is available in Table S9 of Supplementary appendix to Arabi YM et al. Middle East Respiratory Syndrome NEJM 2017 376(6):584594 (http://www.nejm.org/doi/suppl/10.1056/NEJMsr1408795/suppl_file/nejmsr1408795_appendix.pdf).

The effect of corticosteroids on viral clearance of MERS-CoV is unknown, although systemic corticosteroid administration delayed clearance of SARS-CoV and has been associated with prolonged replication of other respiratory viruses. Consequently, serial viral load sampling with PCR testing should be performed in any MERS patients who receive corticosteroids for any indication. A retrospective analysis of data from SARS patients treated with corticosteroids suggested increased mortality. 5.5 Combination therapies

Therapeutic agents were used in multiple combinations for treatment of SARS patients, and increasingly in MERS patients, but there remain inadequate clinical data to disentangle the effects of individual agents from the possible benefits of any combinations. The vast majority of experience is from retrospective observational studies. Limited data from in vitro and animal studies of MERS-CoV infection suggests a possible synergistic effect from combining high doses of interferon (IFN) and intravenous ribavirin. However, the doses of ribavirin used are much higher than those used to treat hepatitis C virus infection. Ribavirin has also been associated with significant adverse effects in both SARS and MERS patients. Available data are inadequate to decide whether any benefit conferred by an interferon/ribavirin synergy outweighs the risk of ribavirin toxicity. Therefore, this combination is not recommended unless it is used in an appropriately planned clinical trial (see https://isaric.tghn.org/articles/adapted-study-documents-protocols/ for open access protocols). Table 1. Evidence base for specific therapies for MERS-CoV infection: Benefit is likely to exceed risk

- SARS *in vitro* (SIV); SARS animal (SA); SARS clinical (SC); MERS-CoV *in vitro* (MIV); MERS animal (MA); MERS clinical (MC)

| Therapy | Studies * Performed | Data: SARS and other respiratory viruses | Data: MERS | Safety Profile | UK feasibility | |---------|---------------------|------------------------------------------|------------|---------------|----------------| | Convalescent plasma (or high neutralizing antibody titre products) | SIV; SA; SC; MIV; MA | RCT not performed in SARS. One RCT supports use of hyperimmune globulin in severe A(H1N1)pdm09 influenza. Observational data suggests efficacy in SARS and A(H1N1)pdm09 and other influenza virus infections. A pooled meta-analysis including SARS-CoV and influenza studies showed a significantly lower risk of mortality in those treated with convalescent plasma or serum. | *In vitro* neutralizing effect based on levels of MERS-CoV specific antibodies and high-titer camel serum improved viral clearance in infected mice. A clinical trial is ongoing but has not yet recruited any patients (NCT02190799). There may be wide variation in the amount of neutralizing antibody depending on illness severity and the timing of plasma collection in relation to convalescence, with waning titres over time. Serologic data from 17 South Korean MERS patients demonstrated robust neutralizing antibody responses by day 21 of illness in the majority of severely ill patients, however, this was not found in patients with milder infection. | Good safety profile in UK, risks as for other blood products. Convalescent plasma should be tested to have documented specific MERS antibody before use with assessment of antibody titres. Potential donors of convalescent sera should wait until at least 3 weeks after their symptom onset. Antibody levels will likely decline with time, as seen in one patient whose antibody response was measured longitudinally. | Availability depends on UK epidemiological situation. The largest Saudi study to identify donors to date showed that MERS antibodies are rarely positive following infection or exposure. Screening of 170 Saudi blood donors showed 0% seroprevalence. Please contact PHE for an update on availability. | | Therapy | Studies * Performed | Data: SARS and other respiratory viruses | Data: MERS | Safety Profile | UK feasibility | |--------------|---------------------|------------------------------------------|---------------------------------------------------------------------------|--------------------------------------------------------------------------------|--------------------------------------------------------------------------------| | Interferons (IFNs) | SIV; SA; SC; MIV; MA; MC | Type I (α, β), type II (γ), and type III (λ) IFNs show activity against SARS in extensive *in vitro* and limited animal and observational clinical studies. | *In vitro*, MERS-CoV appears to be more sensitive to Type I IFNs than SARS-CoV, especially IFN-β<sup>M17-20</sup>. Some animal evidence from marmoset model in severe disease with IFN-β<sub>1b</sub><sup>M25</sup>. Animal studies with Poly IC topical IFN inducer suggest efficacy<sup>M26</sup>. Type 1 IFNs are among the most active drugs at clinically achievable serum levels<sup>M26</sup>. IFN-α in combination with very high-dose ribavirin shows some efficacy in non-human primates but this animal model does not accurately reflect severe MERS illness seen in humans<sup>M27</sup>. A phase II/III trial of lopinavir-ritonavir and IFNβ-1b is open to recruitment in Kingdom of Saudi Arabia (NCT 02845843). | Well established agent. Clinicians experienced in managing side effects should be consulted e.g. those treating hepatitis C virus (HCV) infection and multiple sclerosis. Consideration should be given to shorter-acting preparations compared to peg-IFNs. | Injectable recombinant IFN-β1b is currently first choice and is routinely available. Subcutaneous IFNβ-1b is being trailed in Saudi Arabia. Inhaled IFN-β is currently in Phase II trials but has not been adequately studied in severe lower respiratory tract infections. | | Therapy | Studies * Performed | Data: SARS and other respiratory viruses | Data: MERS | Safety Profile | UK feasibility | |---------|---------------------|------------------------------------------|-------------|---------------|----------------| | **Lopinavir** | SIV; SA; SC; MIV; MA; MC | Limited data that HIV protease inhibitors have *in vitro* anti-SARS-CoV effect(^5). Observational studies suggest clinical benefits in SARS patients treated with lopinavir/ritonavir, including a reduction in mortality reported in one study(^1,2). | Lopinavir inhibitory for MERS-CoV *in vitro* at concentrations observed in blood during clinical use (note other HIV PIs tested, atazanavir and ritonavir, were inactive)(^6). Good *in vivo* evidence from marmoset model for improved outcomes(^7). Use in one patient alongside IFN and ribavirin(^8). Lopinavir-ritonavir was administered with ribavirin and PEG-IFN-α2a to many patients in the South Korea outbreak but outside the context of a clinical trial; unable to determine efficacy(^8). A phase II/III trial of lopinavir-ritonavir and IFNβ-1b is open to recruitment in Kingdom of Saudi Arabia (NCT 02845843). | Well established agent with favourable toxicity profile. Gastrointestinal side effects are common but self-limiting. | Routinely available (as lopinavir and ritonavir combination preparation). | | Therapy | Studies * Performed | Data: SARS and other respiratory viruses | Data: MERS | Safety Profile | UK feasibility | |---------------------------------------------|---------------------|------------------------------------------|---------------------------------------------------------------------------|--------------------------------------------------------------------------------|--------------------------------------------------------------------------------| | **Monoclonal and polyclonal neutralising antibodies (mAbs)** | SIV; SA; MIV; MA | Strong *in vitro* neutralising effect against the SARS-CoV spike protein<sup>P1,2</sup>. | Novel monoclonal antibodies to MERS-CoV spike protein have strong neutralising effect<sup>P3-5</sup>. Potent MERS-CoV– neutralizing antibody have recently been isolated from memory B cells of an infected individual<sup>P6</sup> and polyclonal human neutralizing antibodies have been produced in transchromosomal bovines<sup>P7</sup>. Camel antibodies have been successful in prophylactic and therapeutic use in murine models<sup>P8</sup>. Human mAbs have been successfully trialed as both therapy and prophylaxis in murine models<sup>P9</sup>. Intravenous human mAb 3B11-N reduces radiological evidence of pneumonia in rhesus macaques when given as prophylaxis<sup>P10</sup>. | A Phase 1 clinical trial assessing safety and tolerability of SAB-301 is ongoing (NCT 02788188). In those products which have satisfied UK regulatory safety requirements, benefit is likely to exceed risk. | Contact PHE for an update on availability. Use should be within a trial, or if not possible, through a compassionate use arrangement. | | Therapy | Studies * Performed | Data: SARS and other respiratory viruses | Data: MERS | Safety Profile | UK feasibility | |---------------------------------------------|---------------------|------------------------------------------|---------------------------------------------------------------------------|----------------|----------------| | Monoclonal and polyclonal neutralising antibodies (mAbs) - continued | SIV; SA; MIV; MA | - | Monoclonal antibody resistant mutants (MARMS) selected *in vitro* are not inhibited *in vivo* and show little loss of fitness. A Phase 1 clinical trial has been initiated for SAB-301 (NCT 02788188). Phase 1 trials are expected to commence for LCA60, REGN3051 & REGN3048. | - | - | Table 2. Evidence base for specific therapies for MERS-CoV infection: Data is inadequate for assessment

- SARS *in vitro* (SIV); SARS animal (SA); SARS clinical (SC); MERS-CoV *in vitro* (MIV); MERS animal (MA); MERS clinical (MC)

| Therapy | Studies * Performed | Data: SARS and other respiratory viruses | Data: MERS | Safety Profile | UK feasibility | |---------|---------------------|----------------------------------------|------------|---------------|----------------| | Interferon + ribavirin (combination therapy) | SIV; SA; SC; MIV; MA; MC | Synergistic effect *in vitro* and in animal model when ribavirin combined with IFN-β<sup>M7,12</sup>. Effect of combination could not be distinguished from other concurrent treatments in SARS patients, Where outcomes could be determined, adverse effects were reported<sup>M7</sup>. | IFN-α2b and ribavirin combined *in vitro* had anti-MERS-CoV effect at lower concentration than when used separately<sup>M17</sup>. Combination high dose IFN-α2b and IV ribavirin in MERS rhesus macaque model led to some clinical, radiographic and virological improvements<sup>M17</sup>. IFN/ribavirin combination therapy given late in illness to 5 MERS patients did not prevent death<sup>M22</sup>, and was not helpful in a further 3 out of 6 cases<sup>M24</sup>. Some case reports of apparent benefit when used for early therapy<sup>M24</sup> or post-contact prophylaxis<sup>M30</sup> but there have been case studies that show little effect on mortality<sup>M28,29</sup>. | Adverse effects of ribavirin were frequent in SARS clinical studies (see ribavirin, below)<sup>T1,12,13</sup>. In combination studies, the experimental ribavirin concentrations were higher than those achievable clinically during treatment of hepatitis C<sup>M26</sup>. One retrospective cohort of 20 patients showed no increase in adverse effects apart from greater haemoglobin reduction<sup>M23</sup>. The largest Saudi Arabian cohort demonstrated no benefit with IFN/ribavirin combination, and possible harm with ribavirin<sup>T18</sup>. | Routinely available. Data are inadequate to decide whether any benefit conferred by possible interferon and ribavirin synergy outweighs the risk of ribavirin toxicity, however expert opinion is to not use ribavirin, and if used should be in the context of a clinical trial. | | Therapy | Studies * Performed | Data: SARS and other respiratory viruses | Data: MERS | Safety Profile | UK feasibility | |---------|---------------------|----------------------------------------|-------------|----------------|----------------| | **Interferon + ribavirin (combination therapy) - continued** | SIV; SA; SC; MIV; MA; MC | - | One retrospective cohort study showed improved outcomes in severe MERS-CoV infection in those given ribavirin and IFN-α2a at 14 days but not 28\\textsuperscript{M23}. IFNβ showed the strongest inhibition in vitro compared with IFNα, additionally IFN-α2a may be less inhibitory than IFN-α2b (higher IC\\textsubscript{50}\\textsuperscript{M20}). A further case note review from Saudi Arabia saw patients given IFNα or IFNβ in combination with ribavirin but was an uncontrolled retrospective chart review so no conclusions can be drawn\\textsuperscript{M31}. | - | - | | Therapy | Studies * Performed | Data: SARS and other respiratory viruses | Data: MERS | Safety Profile | UK feasibility | |---------|---------------------|----------------------------------------|-------------|---------------|----------------| | GS-5734 (Nucleoside viral polymerase inhibitor) | SIV; MIV; SA, MA | Polymerase inhibitor with *in vitro* activity against a number of RNA viruses(^1). 90 % Inhibition at ≤150nmol against SARS-CoV in a human airway epithelial cell (HAE) model, with average IC(_{50}) values of 0.069 µM(^2,3). Prophylactic use reduces SARS-CoV lung titres and disease in mice. Early therapeutic use significantly reduced viral titres in lung, and improved lung function on day 3(^3), later use reduced viral load but did not affect clinical outcome – this may be due to the truncated course of disease in murine models. | 90 % Inhibition at ≤150nmol against MERS-CoV in a human airway epithelial cell (HAE) model with average IC(_{50}) values of 0.074 µM(^2,3). Prophylactic intravenous use in 6 Rhesus macaques was associated with reduced MERS-CoV viral loads and reduction of respiratory symptoms(^4). | Manufacturer reports two phase 1 trials completed results not available. Phase 2 trial involving Ebola Virus Disease (EVD) survivors is ongoing (NCT 02818582). | Currently unlicensed. Has been used compassionately for the treatment of EVD in two patients(^5,6). | | BCX4430 (Nucleoside viral polymerase inhibitor) | SIV, MIV | Polymerase inhibitor with *in vitro* activity against a number of RNA viruses. Inhibitory activity against SARS CoV *in vitro*(^5). | Inhibitory activity against MERS CoV *in vitro*(^5). | Phase 1 trial completed but results not available (NCT02319772). | Currently unlicensed. No record of compassionate use for any condition to date. | | Therapy | Studies * Performed | Data: SARS and other respiratory viruses | Data: MERS | Safety Profile | UK feasibility | |--------------|---------------------|------------------------------------------|---------------------------------------------------------------------------|-------------------------------------------------------------------------------|----------------------| | Nitazoxanide | MIV | No SARS data. An RCT showed benefit in uncomplicated influenza in adults(^{R1}). Inhibitory for two non-human CoVs \\textit{in vitro} (^{R2,3}). | Nitazoxanide, and the metabolite tizoxanide, have been shown to inhibit MERS-CoV cultured in LLC-MK2 cells at IC(\_{50})s are similar to those observed for influenza and other viruses (^{R4}). No animal model data available. | Well established agent with defined safety profile. | Routinely available. | | Chloroquine | SIV;MIV | Inhibitory \\textit{in vitro} for multiple viruses including influenza (^{D1,2}). No consistent activity in animal models of influenza (^{D2,3}) and negative results in one influenza RCT of seasonal prophylaxis (^{D4}). | Inhibits MERS-CoV \\textit{in vitro}, with a concentration achievable by standard clinical oral dosing, described in several papers (^{D5}). | Well established agent with defined safety profile. | Routinely available. | Table 3. Evidence base for specific therapies for MERS-CoV infection: Risk is likely to exceed benefit

- SARS *in vitro* (SIV); SARS animal (SA); SARS clinical (SC); MERS-CoV *in vitro* (MIV); MERS animal (MA); MERS clinical (MC)

| Therapy | Studies * Performed | Data: SARS and other respiratory viruses | Data: MERS | Safety Profile | UK feasibility | |---------|---------------------|------------------------------------------|------------|---------------|----------------| | Corticosteroids (as specific therapy for MERS-CoV infection) | SA; SC; MC | A SARS-CoV animal study suggests early anti-inflammatory effects but found ongoing administration may enhance viral replication in the lung. SARS clinical studies have not demonstrated consistent mortality benefits. Some observational studies found clinical improvements after treatment but one RCT found increased viral load associated with corticosteroid treatment. A retrospective analysis suggests that glucocorticoids may be associated with increased mortality in SARS. | No studies available. Given to many MERS patients under uncontrolled circumstances with limited outcome data. Corticosteroids have been used to treat a late complication of MERS-CoV infection (organizing pneumonia) without apparent adverse effect, but at a time when MERS-CoV was no longer detectable in the affected individual. A conference abstract of one large retrospective Saudi Arabian cohort showed a model-dependent decrease in mortality following adjustment for disease severity, however further analysis (personal communication - manuscript currently under review) showed no association on mortality, with a delay in viral RNA clearance. | SARS studies found no mortality benefit and evidence for adverse effects of systemic steroids, with both acute and long-term harms, including delayed viral clearing reported, and increased opportunistic infections. Osteonecrosis was observed following pulsed methylprednisolone, more commonly in male, young patients, and in those receiving more than one administration. | Routinely available. | | Therapy | Studies * Performed | Data: SARS and other respiratory viruses | Data: MERS | Safety Profile | UK feasibility | |---------|---------------------|------------------------------------------|-------------|----------------|----------------| | **Corticosteroids (as specific therapy for MERS-CoV infection) - continued** | - | Use of systemic corticosteroids in patients with severe influenza A(H1N1)pdm09 was also associated with increased risks of prolonged lower respiratory tract viral replication, nosocomial infections, ventilator-associated pneumonia, and higher mortality in observational studies. | - | - | - | | Therapy | Studies * Performed | Data: SARS and other respiratory viruses | Data: MERS | Safety Profile | UK feasibility | |-------------------------|---------------------|------------------------------------------|---------------------------------------------------------------------------|-------------------------------------------------------------------------------|----------------------| | Ribavirin – monotherapy | SIV; SA; SC; MIV; MC| Four of six *in vitro* SARS studies found an antiviral effect(^1). No virological effects were found on SARS in animal models as monotherapy. In SARS clinical studies, the effect of ribavirin could not be distinguished from the effects of other therapies(^{1,13}). | MERS-CoV is inhibited by ribavirin at very high concentrations *in vitro*. These exceed concentrations achievable during clinical use, except possibly for high IV dosages(^{14}). No animal monotherapy studies have been conducted. Combination therapy including ribavirin was given to five MERS patients late in the illness and did not prevent death(^{5}). One recent review suggests that decreased mortality at 14 days seen in combination therapy may be associated with the use of oral ribavirin, but this is speculative(^{10}). | Studies of ribavirin in large numbers of SARS patients found frequent adverse effects including haemolysis, metabolic disturbances, and liver function test derangement(^{1,13}). | Routinely available. | | Therapy | Studies * Performe | Data: SARS and other respiratory viruses | Data: MERS | Safety Profile | UK feasibility | |---------|-------------------|----------------------------------------|-------------|---------------|----------------| | **UK intravenous human normal immunoglobulin (IVIG)** | SC; MIV; MC | Five SARS studies conducted; all inconclusive as used IVIG as part of combination therapy(^{N1}). In one uncontrolled study in Hong Kong, 12 patients who had deteriorated despite other therapies were given IVIG as an additional therapy, with evidence of subsequent improvement(^{N2}). | PHE evaluation shows that IVIG available in the UK has no evidence of MERS-CoV neutralising activity (unpublished data). IVIG from endemic countries requires separate evaluation. Local IVIG was given to correct platelet imbalance in one Saudi patient (along with high dose corticosteroids), with favourable outcome(^{N3}). | Commercial IVIG products have been associated with rare acute renal failure and thromboembolic events(^{N4}). | Routinely available. | | **Mycophenolic acid / mycophenolate mofetil (MMF)** | SIV; SA; MIV; MA; MC | No effect on SARS-CoV \\textit{in vitro} or in a murine model(^{Q1}). | Inhibits MERS-CoV \\textit{in vitro}, with a concentration achievable by standard clinical oral dosing(^{Q2,3}). Synergy in vitro with IFN-(\\beta)(^{Q3}). MERS-CoV marmoset studies indicate that MMF used alone may increase viral replication and worsen outcomes(^{Q4}). One patient acquired infection while on MMF following renal transplantation but survived with reduction in dose(^{Q5}). | Effect of transient immunosuppressive activity in this context is uncertain. Established treatment with multiple well characterised side effects. | Routinely available. | 6 Feedback

As this is a document intended for continual update, we are particularly interested in the views of those who may be using it on the frontline of service. Please send thoughts or suggestions for improvement, or any other comments, to colin.brown@phe.gov.uk and maria.zambon@phe.gov.uk.

7 Useful links

PHE – https://www.gov.uk/government/collections/middle-east-respiratory-syndrome-coronavirus-mers-cov-clinical-management-and-guidance

ISARIC – http://www.isaric.org

WHO – http://www.who.int/emergencies/mers-cov/en/

ECDC – www.ecdc.europa.eu/en/healthtopics/coronavirus-infections/pages/index.aspx

CDC – www.cdc.gov/features/novelcoronavirus/

8 Document authors

Dr Colin S Brown¹,² Dr Gail Carson³ Dr Meera Chand¹,⁴ Dr Jake Dunning¹,³,⁵ Dr Antonia Scobie¹ Professor Maria Zambon¹

¹ National Infection Service, Public Health England, UK ² Department of Infection, Royal Free London NHS Foundation Trust, UK ³ International Severe Acute Respiratory & Emerging Infection Consortium (ISARIC), UK ⁴ Department of Infection, Guy’s & St Thomas’ Hospitals NHS Foundation Trust, UK ⁵ Centre for Tropical Medicine and Global Health, University of Oxford, UK

Colin Brown, Gail Carson, Meera Chand, and Maria Zambon wrote version 1, with significant input from Jake Dunning as an expert adviser. Versions 2 and 3 were revised by Colin Brown, Gail Carson, Meera Chand, Jake Dunning and Maria Zambon. Version 4 was revised by all current authors, with particular updates from Antonia Scobie, Colin Brown and Jake Dunning. 9 Consultation

The following coronavirus experts and clinicians and scientists with experience of SARS, MERS and other respiratory viruses were involved in PHE or ISARIC teleconferences or commented on drafts of this document. We are most grateful to them all for their valued input. This is a document intended for continual update.

Contributors involved in literature review, documentation, and draft development: Ken Baillie\*, University of Edinburgh, UK & ISARIC Working Group 3 chair Nick Barrett, Guy’s & St Thomas’ Hospitals NHS Foundation Trust Katrina Barlow, Public Health England, UK Nichola Goddard, Public Health England, UK Eli Harris, Oxford University, UK Kajsa-Stina Longuere, ISARIC Coordinating Centre, UK Nick Phin, Public Health England, UK John Watson, Public Health England, UK

International experts invited to comment on basis of experience of SARS/H5N1/MERS/ critical care, or to contribute unpublished data: Neil Adhikari, Sunnybrook Research Institute, Canada Yaseen Arabi\*, King Saud Bin Abdulaziz University for Health Sciences, Saudi Arabia Abdullah Brooks, Johns Hopkins University, US & ISARIC past chair Janet Diaz, California Pacific Medical Center, US Jeremy Farrar\*, Director, Wellcome Trust, UK Heinz Feldman, National Institute of Allergy and Infectious Diseases, NIH, US Ron Fouchier, Erasmus Medical Center, The Netherlands Rob Fowler, University of Toronto, Canada & ISARIC Bart Haagmans, Erasmus Medical Center, The Netherlands Frederick Hayden\*, University of Virginia School of Medicine, US & ISARIC past chair David Hui, Chinese University of Hong Kong, China Michael Ison, Northwestern University Feinberg School of Medicine, US Myoung-don Oh\* Seoul National University Hospital, Seoul, South Korea Eric Snijder, University Medical Center Leiden, The Netherlands

WHO staff: Nikki Shindo, World Health Organization, Switzerland Maria Van Kerkhove\*, World Health Organization, Switzerland

\*Contributed to the latest version of this document

Clinicians, virologists, health professionals, and public health experts involved in managing MERS patients: many thanks to all who participated in the PHE and ISARIC/WHO teleconferences for their valuable input. 10 Bibliography: Articles of Interest

A. Antibiotics

1. Sung JJ, Wu A, Joynt GM, et al. Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak. *Thorax* 2004;59(5):414-20. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1746995/pdf/v059p00414.pdf

B. Antiviral peptides/proteins

1. Sung JJ, Wu A, Joynt GM, et al. AVPdb: a database of experimentally validated antiviral peptides targeting medically important viruses. *Nucleic Acids Res* 2014;42(Database issue):D1147-53. Download the PDF from: http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=24285301

2. Channappanavar R, Lu L, Xia S, Du L, Meyerholz DK, Perlman S, Jiang S. Protective Effect of Intranasal Regimens Containing Peptidic Middle East Respiratory Syndrome Coronavirus Fusion Inhibitor Against MERS-CoV Infection. *J Infect Dis* 2015; pii: jiv325. Download the PDF from: http://www.jid.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=26164863

3. Xia S, Liu Q, Wang Q, et al. Middle East respiratory syndrome coronavirus (MERS-CoV) entry inhibitors targeting spike protein. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S0168170214004122

C. BCX4430

1. Warren TK, Wells, J, Panchal RG et al. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. *Nature* 2014; 508, 402–405. Download the PDF from: http://www.nature.com/nature/journal/v508/n7496/pdf/nature13027.pdf

2. Taylor R, Kotian, P, Warren T et al. BCX4430 – A broad-spectrum antiviral adenosine nucleoside analog under development for the treatment of Ebola virus disease. *J infect Pub Health* 2016; 9, 220—226. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S1876034116300193

D. Chloroquine

1. Ooi EE, Chew JS, Loh JP, Chua RC. In vitro inhibition of human influenza A virus replication by chloroquine. *Virol J* 2006;3:39. Download the PDF from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1481635/pdf/1743-422X-3-39.pdf

2. Vigerust DJ, McCullers JA. Chloroquine is effective against influenza A virus in vitro but not in vivo. *Influenza Other Respi Viruses* 2007;1(5-6):189-92. Download the PDF from: Information for Clinicians. Clinical decision-making support for treatment of MERS-CoV patients.

http://onlinelibrary.wiley.com/doi/10.1111/j.1750-2659.2007.00027.x/pdf

3. Yan Y, Zou Z, Sun Y, et al. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Res 2013; 23(2):300–302. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567830/pdf/cr2012165a.pdf

4. Paton NI, Lee L, Xu Y, et al. Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial. Lancet Infect Dis 2011;11(9):677-83. Download the PDF from: http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(11)70065-2/fulltext

5. Dyall J, Coleman CM, Hart BJ, et al. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother 2014;58(8):4885-93. Download the PDF from: http://aac.asm.org/content/58/8/4885.long

E. Convalescent plasma

01. Hung IF, To KK, Lee CK, et al. Hyperimmune Intravenous Immunoglobulin Treatment: A Multicentre Double-Blind Randomized Controlled Trial for Patients with Severe A(H1N1)pdm09 Infection. Chest 2013;144(2):464-473. Download the PDF from: http://journal.publications.chestnet.org/article.aspx?articleid=1656407

02. Cheng Y, Wong R, Soo YO, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. European J Clin Micro 2005;24(1):44-6. Download the PDF from: http://download.springer.com/static/pdf/506/art%253A10.1007%252Fs10096-004-1271-9.pdf?auth66=1362220920_4b68188c5ad3755a49b8647b565fa1d9&ext=.pdf

03. ter Meulen J, Bakker AB, van den Brink EN, et al. Human monoclonal antibody as prophylaxis for SARS coronavirus infection in ferrets. Lancet 2004;363(9427):2139-41. Download the PDF from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(04)16506-9/fulltext

04. Roberts A, Thomas WD, Guarner J, et al. Therapy with a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody reduces disease severity and viral burden in golden Syrian hamsters. J Infect Dis 2006;193(5):685-92. Download the PDF from: http://jid.oxfordjournals.org/content/193/5/685.long

05. Soo YO, Cheng Y, Wong R, et al. Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect 2004;10(7):676-8. Download the PDF from: http://onlinelibrary.wiley.com/doi/10.1111/j.1469-0691.2004.00956.x/pdf

06. Hung IF, To KK, Lee CK, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis 2011 Feb 15;52(4):447-56. Download the PDF from: http://cid.oxfordjournals.org/content/52/4/447.long

07. Mair-Jenkins J, Saavedra-Campos M, Baillie K, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral aetiology: a systematic review and exploratory meta-analysis. *J Infect Dis* 2015;211(1):80-90. Download the PDF from http://jid.oxfordjournals.org/content/early/2014/07/16/infdis.jiu396.full.pdf+html

08. Yeh KM, Chiuheh TS, Siu LK, et al. Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a Taiwan hospital. *J Antimicrob Chemother* 2005;56(5):919-22. Download the PDF from: http://jac.oxfordjournals.org/content/56/5/919.full.pdf+html

09. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. *PLoS Med* 2006;3(9):e343. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1564166/pdf/pmed.0030343.pdf

10. Wong SSY, Yuen KY. The management of coronavirus infections with particular reference to SARS. *J Antimicrob Chemother* 2008;62(3):437-41. Download the PDF from: http://jac.oxfordjournals.org/content/62/3/437.full.pdf+html

11. Du L, Zhao G, Yang Y, et al. A conformation-dependent neutralizing monoclonal antibody specifically targeting receptorbinding domain in middle East respiratory syndrome coronavirus spike protein. *J Virol* 2014;88:7045–7053. Download the PDF from: http://jvi.asm.org/content/88/12/7045

12. Ying T, Du L, Ju TW, et al. Exceptionally potent neutralization of Middle East respiratory syndrome coronavirus by human monoclonal antibodies. *J Virol* 2014;88:7796 –7805. Download the PDF from: http://jvi.asm.org/content/88/14/7796

13. Jiang L, Wang N, Zuo T, et al. Potent neutralization of MERS-CoV by human neutralizing monoclonal antibodies to the viral spike glycoprotein. *Sci Transl Med* 2014;6:234ra259. Download the PDF from: http://stm.sciencemag.org/content/6/234/234ra59

14. Tang XC, Agnihothram SS, Jiao Y, et al. Identification of human neutralizing antibodies against MERSCoV and their role in virus adaptive evolution. *Proc Natl Acad Sci USA* 2014;111:E2018 –E2026. Download the PDF from: http://www.pnas.org/content/111/19/E2018

15. Corti D, Zhao J, Pedotti M, et al. Prophylactic and postexposure efficacy of a potent human monoclonal antibody against MERS coronavirus. *Proc Natl Acad Sci USA* 2015;112(33):10473-8. Download the PDF from: http://www.pnas.org/content/112/33/10473.long

16. Ying T, Li H, Lu L, Dimitrov DS, Jiang S. Development of human neutralizing monoclonal antibodies for prevention and therapy of MERS-CoV infections. *Microbes Infect* 2015;17(2):142-8. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S1286457914003049 Information for Clinicians. Clinical decision-making support for treatment of MERS-CoV patients.

17. Zhang MY, Choudhry V, Xiao X, Dimitrov DS. Human monoclonal antibodies to the S glycoprotein and related proteins as potential therapeutics for SARS. *Curr Opin Mol Ther* 2005;7(2):151-56. Abstract only: http://www.ncbi.nlm.nih.gov/pubmed/15844623

18. Burton DR, Saphire EO. Swift antibodies to counter emerging viruses. *Proc Natl Acad Sci USA* 2015;112(33):10082-3. Download the PDF from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4547222/pdf/pnas.201513050.pdf

19. Chan KH, Chan JF, Tse H, et al. Cross-reactive antibodies in convalescent SARS patients’ sera against the emerging novel human coronavirus EMC (2012) by both immunofluorescent and neutralizing antibody tests. *J Infect* 2013;67(2):130-140. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S0163445313000716

20. Zhao J, Perera RA, Kayali G, Meyerholz D, Perlman S, Peiris M. Passive immunotherapy with dromedary immune serum in an experimental animal model for Middle East respiratory syndrome coronavirus infection. *J Virol* 2015;89(11):6117-20. Download the PDF from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442417/pdf/zjv6117.pdf

21. Arabi YM, Balkhy HH, Hayden FG, Bouchama A, Luke T, et al. Middle East Respiratory Syndrome. *N Engl J Med* 2017;376(6):584-594. Download PDF from: http://www.nejm.org/doi/full/10.1056/NEJMsr1408795

22. Arabi YM, Hajeer AH, Luke T, et al. Feasibility of using convalescent plasma immunotherapy for MERS-CoV infection, Saudi Arabia. *Emerg Infect Dis* 2016;22:1554-61. Download the PDF from: https://wwwnc.cdc.gov/eid/article/22/9/15-1164_article

23. Park WB, Perera RAPM, Choe PG, et al. Kinetics of Serologic Responses to MERS Coronavirus Infection in Humans, South Korea. *Emerg Infect Dis* 2015;21(12):2186-2189. Download the PDF from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672454

24. Alrashid M, Taleb AA, Hajeer A, Arabi Y. Prevalence of antibodies against the Middle East Respiratory Syndrome coronavirus, influenza A and B viruses among blood donors, Saudi Arabia. *Ann Thorac Med* 2017;12:217-8.

F. Corticosteroids

01. Zhang X, Alekseev K, Jung K, Vlasova A, Hadya N, Saif LJ. Cytokine responses in porcine respiratory coronavirus-infected pigs treated with corticosteroids as a model for severe acute respiratory syndrome. *J Virol* 2008;82(9):4420-8. Download the PDF from: http://europepmc.org/articles/PMC2293053?pdf=render

02. Soo YO, Cheng Y, Wong R, et al. Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. *Clin Microbiol Infect* 2004;10(7):676-8. Download the PDF from: http://onlinelibrary.wiley.com/doi/10.1111/j.1469-0691.2004.00956.x/pdf

03. Sung JJ, Wu A, Joynt GM, et al. Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak. *Thorax* 2004;59(5):414-20. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1746995/pdf/v059p00414.pdf

04. Chen RC, Tang XP, Tan SY, et al. Treatment of Severe Acute Respiratory Syndrome With Glucosteroids: The Guangzhou Experience. *Chest* 2006; 129(6): 1441-1452. Download the PDF from: http://journal.publications.chestnet.org/article.aspx?articleid=1084497

05. Lee N, Allen Chan KC, Hui DS, et al. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. *J Clin Virol* 2004;31(4):304-9. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S1386653204001957

06. Loutfy MR, Blatt LM, Siminovitch KA, et al. Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study. *JAMA* 2003;290(24):3222-8. Download the PDF from: http://jama.jamanetwork.com/data/Journals/JAMA/4909/JPC30087.pdf

07. Auyeung TW, Lee JS, Lai WK, et al. The use of corticosteroid as treatment in SARS was associated with adverse outcomes: a retrospective cohort study. *J Infect* 2005;51:98-102. Download the PDF from: http://europepmc.org/abstract/med/16038758

08. Kim SH, Hong SB, Yun SC, et al. Corticosteroid treatment in critically ill patients with pandemic influenza A/H1N1 2009 infection: analytic strategy using propensity scores. *Am J Respir Crit Care Med* 2011;183(9):1207-14. Download the PDF from: http://www.atsjournals.org/doi/pdf/10.1164/rccm.201101-0110OC

09. Arabi YM, Arifi AA, Balkhy et al. Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection. *Ann Intern Med* 2014;160(6):389-97. Download the PDF from: http://annals.org/aim/article/1817260/clinical-course-outcomes-critically-ill-patients-middle-east-respiratory-syndrome

10. Wong SSY, Yuen KY. The management of coronavirus infections with particular reference to SARS. *J Antimicrob Chemoth* 2008;62(3):437-41. Download the PDF from: http://jac.oxfordjournals.org/content/62/3/437.full.pdf+html

11. Levy MM, Baylor MS, Bernard GR, et al. Clinical issues and research in respiratory failure from severe acute respiratory syndrome. *Am J Resp Crit Care* 2005;171(5):518-26. Download the PDF from: http://www.atsjournals.org/doi/abs/10.1164/rccm.200405-621WS

12. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. *PLoS Med* 2006;3(9):e343. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1564166/pdf/pmed.0030343.pdf

13. Griffith JF, Antonio GE, Kumta SM, et al. Osteonecrosis of hip and knee in patients with severe acute respiratory syndrome treated with steroids. Radiology 2005;235(1):168-75. Download the PDF from: http://pubs.rsna.org/doi/pdf/10.1148/radiol.2351040100

14. Guo KJ, Zhao FC, Guo Y, Li FL, Zhu L, Zheng W. The influence of age, gender and treatment with steroids on the incidence of osteonecrosis of the femoral head during the management of severe acute respiratory syndrome: a retrospective study. Bone Joint J 2014;96-B(2):259-62. Download the PDF from: http://www.bjj.boneandjoint.org.uk/content/96-B/2/259

15. Sessler CN, Gay PC. Are corticosteroids useful in late-stage acute respiratory distress syndrome? Respir Care 2010;55(1):43-55. Download the PDF from: http://rc.rcjournal.com/content/55/1/43.short

16. Tang BM, Craig JC, Eslick GD, et al. Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care Med 2009;37(5):1594-603. Download the PDF from: http://criticalcaremedicine.pbworks.com/f/tang+2010+crit+care+med.pdf

17. Khilnani GC, Hadda V. Corticosteroids and ARDS: A review of treatment and prevention evidence. Lung India 2011;28(2):114–119. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109833/?lopi=reader

18. Kim I, Eun Lee J, Kim K-H et al. Successful treatment of suspected organizing pneumonia in a patient with Middle East respiratory syndrome coronavirus infection: a case report. J Thorac Dis 2016;8(10):E1190-E1194. Download the PDF from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107491/pdf/jtd-08-10-E1190.pdf

19. Arabi YM, Mandourah Y, Al-Hameed F, et al. The Association of Corticosteroid therapy and the Outcome of Critically ill Patients with the Middle East Respiratory Syndrome. ATS: Washington, 2017. Abstract 8289. Abstract available from: http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2017.195.1_MeetingAbstracts.A6868

G. Cyclosporin

1. de Wilde AH, Zevenhoven-Dobbe JC, van der Meer Y, et al. Cyclosporin A inhibits the replication of diverse coronaviruses. J Gen Virol 2011;92(Pt 11):2542-8. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352363/

2. Pfefferle S, Schopf J, Kogl M, et al. The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors. PLoS Path 2011;7(10):e1002331. Download the PDF from: http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002331

3. de Wilde AH, Ray VS, Oudshoorn D, et al. Human coronavirus-EMC replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-alpha Information for Clinicians. Clinical decision-making support for treatment of MERS-CoV patients.

treatment. *J Gen Virol* 2013; 94, 1749-1760. Download PDF at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749523/pdf/1749.pdf

4. De Wilde AH, Raj VS, Oudshoom D, et al. MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment. *J Gen Virol* 2013;94(Pt 8):1749–60. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749523/pdf/1749.pdf

5. AlGhamdi M, Mushtaq F, Awn N, Shalhoub S. MERS CoV infection in two renal transplant recipients: case report. *Am J Transplant* 2015;15:1101-4. Download the PDF from: http://dx.doi.org/10.1111/ajt.13085

**H. Cytokines and chemokines**

1. Glass WG, Subbarao K, Murphy B, Murphy PM. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. *J Immunol* 2004;173(6):4030-39. Download the PDF from: http://www.jimmunol.org/content/173/6/4030.full.pdf+html

2. Wong CK, Lam CW, Wu AK, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. *Clinical Exp Immunol* 2004;136(1):95-103. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1808997/pdf/cei0136-0095.pdf

3. Lau SKP, Lau CCY, Chan K, et al. Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment. *J Gen Virol* 2013;94(12):2679-2690. Download the PDF from: http://vir.sgmjournals.org/content/94/Pt_12/2679.full.pdf+html

4. Shirato K, Kawese M, Matsuyama S. Middle East Respiratory Syndrome Coronavirus Infection Mediated by the Transmembrane Serine Protease TMPRSS2. *J Virol* 2013; 87 (23):12552-61. Download the PDF from: http://jvi.asm.org/content/87/23/12552.full.pdf+html

**I. General**

01. Bosma KJ, Taneja R, Lewis JF. Pharmacotherapy for prevention and treatment of acute respiratory distress syndrome: Current and experimental approaches. *Drugs* 2010;70(10):1255-82. Abstract only: http://www.ncbi.nlm.nih.gov/pubmed/20568833

02. DuVernoy T, Briese T, et al. Panel discussion - Viral respiratory pathogens. *Influenza Other Respi Viruses* 2010;4:21-22. Download the PDF from: http://onlinelibrary.wiley.com/doi/10.1111/j.1750-2659.2010.00136.x/pdf

03. Barnard DL, Kumaki Y. Recent developments in anti-severe acute respiratory syndrome coronavirus chemotherapy. *Future Virol* 2011;6(5):615-31. Download the PDF from: http://europepmc.org/articles/PMC3136164/ Information for Clinicians. Clinical decision-making support for treatment of MERS-CoV patients.

04. Josset L, Menachery VD, Gralinski LE, et al. Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus. *mBio* 2013;4(3):e00165-13. Download the PDF from: http://mbio.asm.org/content/4/3/e00165-13

05. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. *Crit Care Med* 2008; 36:296–327. Download the PDF from: http://www.survivingsepsis.org/Guidelines/Pages/default.aspx

06. World Health Organization. Interim Guidance Document - updated July 2015. Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do. Geneva: WHO, 2015. Download the PDF from: http://www.who.int/csr/disease/coronavirus_infections/case-management-ipc/en/

07. Hayden FG. Advances in antivirals for non-influenza respiratory virus infections. *Influenza Other Respi Viruses* 2013;7(Suppl. 3): 36–43. Download the PDF from: http://onlinelibrary.wiley.com/doi/10.1111/irv.12173/pdf

08. Cheng VCC, Chan JFW, To KKKW, Yuen KY. Clinical management and infection control of SARS: lessons learned. *Antivir Res* 2013;100:407-419. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S0166354213002246

09. Momattin H, Mohammed K, Zumla A, Memish ZA, Al-Tawfiq JA. Therapeutic Options for MERS-CoV – possible lessons from a systematic review of SARS-CoV therapy. *Int J Infect Dis* 2013;17:e792–e798. Download the PDF from: http://www.ijidonline.com/article/S1201-9712(13)00229-4/pdf

10. Hui DS, Memish ZA, Zumla A. Severe acute respiratory syndrome vs. the Middle East respiratory syndrome. *Curr Opin Pulm Med* 2014;20(3):233-41. Download the PDF from: http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1070-5287&volume=20&issue=3&spage=233

11. Sharif-Yakan A, Kanj SS. Emergence of MERS-CoV in the Middle East: origins, transmission, treatment, and perspectives. *PLoS Pathog* 2014;10(12):e1004457. Download the PDF from: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004457

12. Dyall J, Coleman CM, Hart BJ, et al. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. *Antimicrob Agents Chemother* 2014;58(8):4885-93. Download the PDF from: http://aac.asm.org/content/58/8/4885.long

13. Memish ZA, Assiri A, Alhakeem R, et al. Middle East Respiratory Syndrome Corona virus, MERS-CoV. Conclusions from the 2nd Scientific Advisory Board Meeting of the WHO Collaborating Center for Mass Gathering Medicine, Riyadh. *Int J Infect Dis* 2014;24:51-3. Download the PDF from: http://www.ijidonline.com/article/S1201-9712(14)01491-X/pdf

14. Al-Tawfiq JA, Memish ZA. What are our pharmacotherapeutic options for MERS-CoV? *Expert Rev Clin Pharmacol* 2014;7(3):235-8. Download the PDF from: http://www.tandfonline.com/doi/full/10.1586/17512433.2014.890515

15. Chan JF, Lau SK, To KK, Cheng VC, Woo PC, Yuen KY. Middle East Respiratory Syndrome Coronavirus: Another Zoonotic Betacoronavirus Causing SARS-Like Disease. *Clin Microbiol Rev* 2015;28(2):465-522. Download the PDF from: http://cmr.asm.org/cgi/pmidlookup?view=long&pmid=25810418

16. Zumla A, Hui DS, Perlman S. Middle East respiratory syndrome. *Lancet* 2015; 386: 995–1007. Download the PDF from: http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(15)60454-8.pdf

17. Mo Y and Fisher D. A review of treatment modalities for Middle East Respiratory Syndrome. *J Antimicrob Chemother* 2016;71(12):3340-3350. Download the PDF from: https://www.ncbi.nlm.nih.gov/pubmed/27585965

18. Chong YP, Song, JY, Seo YB, Shin HS. Antiviral Treatment Guidelines for Middle East Respiratory Syndrome. *Infect Chemother* 2015;47(3):212-222. Download PDF from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607778/

19. Arabi YM, Balkhy HH, Hayden FG, Bouchama A, Luke T, et al. Middle East Respiratory Syndrome. *N Engl J Med* 2017;376(6):584-594. Download PDF from: http://www.nejm.org/doi/full/10.1056/NEJMsr1408795#

20. Al Ghamdi, Alghamdi KM, Ghandoora Y et al. Treatment outcomes for patients with Middle Eastern Respiratory Syndrome Coronavirus (MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia. *BMC Infect Dis* 2016; 16:174. Download PDF from: https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-016-1492-4.

21. Arabi Y, Balkhy H, Hajeer A et al. Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. *SpringerPlus* 2015;4:709. Download PDF from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653124

22. Uyeki TM, Erlandson KJ, Korch G, O’Hara M, Wathen M, Hu-Primmer J, et al. Development of medical countermeasures to Middle East respiratory syndrome coronavirus. *Emerg Infect Dis* 2016;22(7):DOI:10.3201/eid2207.160022. Download PDF from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918159/

23. Zumla A, Azhar El, Arabi A et al. Host-directed therapies for improving poor treatment outcomes associated with the middle east respiratory syndrome coronavirus infections. *Int J* Information for Clinicians. Clinical decision-making support for treatment of MERS-CoV patients.

*Infect Dis* 2015;40:71-4. Download PDF from: http://www.sciencedirect.com/science/article/pii/S1201971215002155

**J. GS-5734**

1. Lo MK, Jordan R, Arvey A et al. GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses. *Sci Rep* 2017;7:43395. Download the PDF from http://www.nature.com/articles/srep43395

2. Sims AC. The small molecule nucleoside prodrug GS-5734 exhibits broad antiviral activity against pathogenic human coronaviruses and related zoonotic strains. 6th Clinical Microbiology Conference: Rome, 2016. Abstract available at: http://clinicalmicrobiology.conferenceseries.com/abstract/2016/the-small-molecule-nucleoside-prodrug-gs-5734-exhibits-broad-antiviral-activity-against-pathogenic-human-coronaviruses-and-related-zoonotic-strains

3. Sheahan TP, Sims AC, Graham RL et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. *Sci Trans Med* 2017;9(396):PII:eaal3653. Download the PDF from: http://stm.sciencemag.org/content/9/396/eaal3653/tab-pdf

4. de Wit E, Feldmann F, Cronin J et al. Intravenous treatment with the nucleoside analog GS-5734 reduces viral lung loads and disease burden in rhesus macaques infected with MERS-CoV. Personal communication (following presentation at American Society for Virology: Virginia, 2016).

5. Jacobs M, Rodger A, Bell DJ et al. Late Ebola virus relapse causing meningoencephalitis: a case report. *Lancet* 2016; 388: 498–503. Download the PDF from: http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(16)30386-5.pdf

6. Dörnemann, J, Burzio C, Ronsse A et al. First Newborn Baby to Receive Experimental Therapies Survives Ebola Virus Disease. *J Infect Dis* 2017;215:171–4. Download the PDF from: https://academic.oup.com/jid/article/215/2/171/2877903/First-Newborn-Baby-to-Receive-Experimental

**K. Herbal medicine**

1. Arastoo M, Khorram Khorshid HR, Radmanesh R, Gharibdoust F. Combination of IMOD and Arbidol to increase their immunomodulatory effects as a novel medicine to prevent and cure influenza and some other infectious diseases. *J Med Hypotheses Ideas* 2014;8:53-36. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S2251729414000032

**L. Indomethacin**

01. Amici C, Di Caro A, Ciucci A, et al. Indomethacin has a potent antiviral activity against SARS coronavirus. *Antiviral Ther* 2006;11(8):1021-30. Download the PDF from: http://www.intmedpress.com/servefile.cfm?uid=35d8dc5e-70f4-491f-acad-e35f99be9211 M. Interferon (IFN)

02. Loutfy MR, Blatt LM, Siminovitch KA, et al. Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study. *JAMA* 2003;290(24):3222-8 Download the PDF from: http://jama.jamanetwork.com/data/Journals/JAMA/4909/JPC30087.pdf

03. Haagmans BL, Kuiken T, Martina BE, et al. Pegylated interferon-α protects type 1 pneumocytes against SARS coronavirus infection in macaques. *Nat Med* 2004;10(3):290-93 Download the PDF from: http://www.nature.com/nm/journal/v10/n3/full/nm1001.html

04. Sainz B, Jr., Mossel EC, Peters CJ, Garry RF. Interferon-beta and interferon-gamma synergistically inhibit the replication of severe acute respiratory syndrome-associated coronavirus (SARS-CoV). *Virology* 2004;329(1):11-7. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S0042682204005422

05. Scagnolari C, Vicenzi E, Bellomi F, et al. Increased sensitivity of SARS-coronavirus to a combination of human type I and type II interferons. *Antivir Ther* 2004;9(6):1003-11. Download the PDF from: http://www.intmedpress.com/serveFile.cfm?sUID=175607d8-e6a4-439e-a9d2-e345e2ec3ef4

06. Barnard DL, Day CW, Bailey K, et al. Evaluation of immunomodulators, interferons and known in vitro SARS-coV inhibitors for inhibition of SARS-coV replication in BALB/c mice. *Antivir Chem Chemother* 2006;17(5):275-84. Download the PDF from: http://www.intmedpress.com/serveFile.cfm?sUID=9ed38ddd-648c-40ad-9a4c-3e4a9a42f562

07. Haagmans BL, Osterhaus ADME. Coronaviruses and their therapy. *Antivir Res* 2006;71(2-3 Spec Iss):397-403. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S0166354206001707

08. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. *PLoS Med* 2006;3(9):e343. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1564166/pdf/pmed.0030343.pdf

09. Cervantes-Barragan L, Züst R, Weber F, et al. Control of coronavirus infection through plasmacytoid dendritic-cell- derived type I interferon. *Blood* 2007;109(3):1131-37. Download the PDF from: http://bloodjournal.hematologylibrary.org/content/109/3/1131.full.pdf

10. Wong CK, Lam CW, Wu AK, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. *Clin Exp Immunol* 2004;136(1):95-103. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1808997/pdf/cei0136-0095.pdf

11. Wong SSY, Yuen KY. The management of coronavirus infections with particular reference to SARS. *J Antimicrob Chemoth* 2008;62(3):437-41. Download the PDF from: http://jac.oxfordjournals.org/content/62/3/437.full.pdf+html

12. Danesh A, Cameron CM, Leon AJ, et al. Early gene expression events in ferrets in response to SARS coronavirus infection versus direct interferon-alpha2b stimulation. *Virology* 2011;409(1):102-Download the PDF from: http://www.sciencedirect.com/science/article/pii/S0042682210006380

13. Morgenstern B, Michaelis M, Baer PC, Doerr HW, Cinatl J Jr. Ribavirin and interferon-beta synergistically inhibit SARS-associated coronavirus replication in animal and human cell lines. *Biochem Biophys Res Commun* 2005 Jan 28;326(4):905-8. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S0006291X04027299

14. Bruno R, Sacchi P, Cima S, et al. Comparison of peginterferon pharmacokinetic and pharmacodynamic profiles. *J Viral Hepatitis* 2012;19 Suppl 1:33-6. Download the PDF from: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2893.2011.01519.x/pdf

15. Cameron MJ, Kelvin AA, Leon AJ, et al. Lack of Innate Interferon Responses during SARS Coronavirus Infection in a Vaccination and Reinfection Ferret Model. *PloS One* 2012;7(9). Download the PDF from: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045842

16. Mordstein M, Neugebauer E, Ditt V, et al. Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections. *J Virol* 2010;84(11):5670-7. Download the PDF from: http://jvi.asm.org/content/84/11/5670.full

17. Kindler E, Jónsdóttir HR, Muth D, et al. Efficient Replication of the Novel Human Betacoronavirus EMC on Primary Human Epithelium Highlights Its Zoonotic Potential. *mBio* 2013;4(1):DOI:10.1128/mBio.00611-12. Download the PDF from: http://mbio.asm.org/content/4/1/e00611-12.full.html

18. Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ, Feldmann H. Inhibition of novel human coronavirus-EMC replication by a combination of interferon-a2b and ribavirin. *Sci Rep* 2013;3(1686);DOI:10.1038/srep01686. Download the PDF from: http://www.biomedsearch.com/attachments/00/23/59/49/23594967/srep01686.pdf

19. de Wilde AH, Ray VS, Oudshoorn D, et al. MERS coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-alpha treatment. *J Gen Virol* 2013;94(Pt 8):1749-60. Download the PDF from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749523/pdf/1749.pdf

20. Chan JF, Chan KH, Kao RY, et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. *J Infect* 2013;67(6):606-16. Download the PDF from: http://www.journalofinfection.com/article/S0163-4453(13)00298-3/pdf

21. Hart BJ, Dyall J, Postnikova E, et al L. Interferon-b and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell based assays. *J Gen Virol* 2014;95:571-577. Download the PDF from: http://vir.sgmjournals.org/content/95/Pt_3/571.full.pdf+html?sid=b01f8c80-bde3-49d9-b716-c9b153f5dddc Information for Clinicians. Clinical decision-making support for treatment of MERS-CoV patients.

22. Adedeji AO, Sarafianos SG. Future treatment strategies for novel Middle East respiratory syndrome coronavirus infection. *Future Med Chem* 2013;5(18):2119–2122. Download the PDF from: http://www.researchgate.net/publication/258827095_Future_treatment_strategies_for_novel_Middle_East_respiratory_syndrome_coronavirus_infection

23. Al-Tawfiq JA, Mommatin H, Dib J, Memish ZA. Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. *Int J Infect Dis* 2014;20:42-6. Download the PDF from: http://dx.doi.org/10.1016/j.ijid.2013.12.003

24. Omrani AS, Saad MM, Baig K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. *Lancet Infect Dis* 2014;14(11):1090-5. Download the PDF from: http://linkinghub.elsevier.com/retrieve/pii/S1473-3099(14)70920-X

25. Khalid M, Khan B, Al Rabiah F, et al. Middle Eastern Respiratory Syndrome Corona Virus (MERS CoV): case reports from a tertiary care hospital in Saudi Arabia. *Ann Saudi Med* 2014;34(5):396-400. Download the PDF from: http://www.annsaudimed.net/files.php?force&file=2014_0435_OA_233141539.pdf

26. Chan JFW, Yao Y, Yeung M-L, et al. Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a non-human primate model of common marmoset. *J Infect Dis* 2015;212(12):1904-13. Download the PDF from: http://jid.oxfordjournals.org/content/early/2015/07/20/infdis.jiv392.short

27. Strayer DR, Dickey R, Carter WA. Sensitivity of SARS/MERS CoV to Interferons and Other Drugs Based on Achievable Serum Concentrations in Humans. *Infect Dis – Drug Targets* 2014;14:1-7. Download the PDF from: http://www.eurekaselect.com/123324/article

28. Falzarano D, de Wit E, Rasmussen AL, et al. Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV–infected rhesus macaques. *Nat Med* 2013;19(10):1313-7. Download the PDF from: http://dx.doi.org/10.1038/nm.3362

29. Shalhoub S, Farahat F, Al-Jiffri A, Simhairi R, Shamma O, Siddiqi N, Mushtaq A. IFN-α2a or IFN-β1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. *J Antimicrob Chemother* 2015;70(7):2129-32. Download the PDF from: http://jac.oxfordjournals.org/content/70/7/2129.full.pdf+html

30. Spanakis N, Tsiodras S, Haagmans BL, et al. Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen. *Int J Antimicrob Agents* 2014;44(6):528-32. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S0924857914002787#

31. Khalid M, Al Rabiah F, Khan B, Al Mobeireek A, Butt TS, Al Mutairy E. Ribavirin and interferon-α2b as primary and preventive treatment for Middle East respiratory syndrome coronavirus: a preliminary report of two cases. *Antivir Ther* 2015;20:87-91. Download the Information for Clinicians. Clinical decision-making support for treatment of MERS-CoV patients.

PDF from: http://www.intmedpress.com/journals/avt/abstract.cfm?id=2792&pid=48

31. Al Ghamdi M, Al Ghamdi M, Ghandoora et al. Treatment outcomes for patients with Middle Eastern Respiratory Syndrome Coronavirus (MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia. *BMC Infect Dis* 2016;16:174. Download PDF from: https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-016-1492-4.

**N. Intravenous Immunoglobulin (IVIG)**

1. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. *PLoS Med* 2006;3(9):e343. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1564166/pdf/pmed.0030343.pdf

2. Ho JC, Wu AY, Lam B, et al. Pentaglobin in steroid-resistant severe acute respiratory syndrome. *Int J Tuberc Lung Dis* 2004: 8(10):1173–1179. Download the PDF from: http://www.ingentaconnect.com/content/iuatld/ijtld/2004/00000008/00000010/art00003

3. Arabi YM, Arifi AA, Balkhy HH, Najm H, Aldawood AS, Ghabashi A, Hawa H, Alothman A, Khaldi A, Al Raiy B. Course and Outcomes of Critically Ill Patients With MERS-CoV Infection. *Ann Intern Med* 2014;160(6):389-97. Download the PDF from: http://www.annals.org/article.aspx?volume=160&issue=6&page=389

4. Katz U, Achiron A, Sherer Y, et al. Safety of intravenous immunoglobulin (IVIG) therapy. *Autoimmun Rev* 2007;6(4):257-9. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S1568997206001352

**O. Mannose-binding lectin**

1. Ip WK, Chan KH, Law HK, et al. Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. *J Infect Dis* 2005;191(10):1697-704. Download the PDF from: http://jid.oxfordjournals.org/content/191/10/1697.full.pdf+html

2. P Zhou Y, Lu K, Pfefferle S, et al. A single asparagine-linked glycosylation site of the severe acute respiratory syndrome coronavirus spike glycoprotein facilitates inhibition by mannose-binding lectin through multiple mechanisms. *J Virol* 2010;84(17):8753-64. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919028/pdf/0554-10.pdf

3. Michelow IC, Lear C, Scully C, et al. High-dose mannose-binding lectin therapy for Ebola virus infection. *J Infect Dis* 2011;203(2):175-9. Download the PDF from: http://jid.oxfordjournals.org/content/203/2/175.full.pdf+html

4. Arabi YM, Arifi AA, Balkhy HH, Najm H, Aldawood AS, Ghabashi A, Hawa H, Alothman A, Khaldi A, Al Raiy B. Course and Outcomes of Critically Ill Patients With MERS-CoV Infection. *Ann Intern Med* 2014;160(6):389-97. Download the PDF from: http://annals.org/aim/article/1817260/clinical-course-outcomes-critically-ill-patients-middle- Information for Clinicians. Clinical decision-making support for treatment of MERS-CoV patients.

5. Rahman E, Sulaiman M, Mohboob M, et al. Fate of Middle East Respiratory Syndrome Coronavirus infection in four haemodiaysis patients in Prince Sultan Military Medical City. *Nephrol Dial Transplant* 2014;29(suppl 3):iii1-iii2S(Poster-P633). Abstract available at: http://www.abstracts2view.com/era_archive/view.php?nu=ERA14L1_103

P. Monoclonal and polyclonal antibodies

01. Zhong X, Yang H, Guo Z, et al. B-Cell Responses in Patients Who Have Recovered from Severe Acute Respiratory Syndrome Target a Dominant Site in the S2 Domain of the Surface Spike Glycoprotein. *J Virol* 2005;79(6):3401-3408. Download the PDF from: http://jvi.asm.org/content/79/6/3401.full

02. Ho JC, Wu AY, Lam B, et al. Pentaglobin in steroid-resistant severe acute respiratory syndrome. *Int J Tuberc Lung Dis* 2004: 8(10):1173–1179. Download the PDF from: http://www.ingentaconnect.com/content/iuatld/ijtld/2004/00000008/00000010/art00003#

03. Du L, Zhao G, Yang Y, et al. A conformation-dependent neutralizing monoclonal antibody specifically targeting receptor binding domain in middle East respiratory syndrome coronavirus spike protein. *J Virol* 2014;88:7045–7053. Download the PDF from: http://jvi.asm.org/content/88/12/7045

04. Jiang L, Wang N, Zuo T, et al. Potent neutralization of MERS-CoV by human neutralizing monoclonal antibodies to the viral spike glycoprotein. *Sci Transl Med* 2014;6:234ra259. Download the PDF from: http://stm.sciencemag.org/content/6/234/234ra59

05. Tang XC, Agnihothram SS, Jiao Y, et al. Identification of human neutralizing antibodies against MERSCoV and their role in virus adaptive evolution. *Proc Natl Acad Sci USA* 2014;111:E2018 –E2026. Download the PDF from: http://www.pnas.org/content/111/19/E2018

06. Corti D, Zhao J, Pedotti M, et al. Prophylactic and postexposure efficacy of a potent human monoclonal antibody against MERS coronavirus. *Proc Natl Acad Sci USA* 2015;112(33):10473-8. Download the PDF from: http://www.pnas.org/content/112/33/10473.long

07. Luke T, Wu H, Zhao J, Channappanavar R, Coleman CM, Jiao JA, Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo. *Sci Transl Med* 2016;8:326. Download the PDF from: https://www.ncbi.nlm.nih.gov/pubmed/26888429

08. Zhao J, Perera RA, Kayali G, Meyerholz D, Perlman S, Peiris M. Passive immunotherapy with dromedary immune serum in an experimental animal model for Middle East respiratory syndrome coronavirus infection. *J Virol* 2015;89(11):6117-20. Download the PDF from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442417/pdf/zjv6117.pdf

09. Pascal KE, Coleman cm, Mujica AO et al. Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection. *Proc Natl Acad Sci USA* 2015;112(28):8738-43. Download the PDF from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507189/pdf/pnas.201510830.pdf

10. Johnson RF, Bagci U, Keith L, et al. 3B11-N, a monoclonal antibody against MERS-CoV, reduces lung pathology in rhesus monkeys following intratracheal inoculation of MERS-CoV Jordan-n3/2012. *Virology* 2016;490:49-58. Download the PDF from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769911/pdf/nihms752288.pdf

11. Dixit R, Herz J, Dalton et al. Benefits of using heterologous polyclonal antibodies and potential applications to new and undertreated infectious pathogens. *Vaccine* 2016;34:1152–1161. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S0264410X16000426

**Q. Mycophenolic Acid (MMF)**

1. Barnard, DL Day CW, Bailey, Heiner, KM et al. Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin. *Antiviral Res* 2006;71:53–63. Download the PDF from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441846/

2. Hart BJ, Dyall J, Postnikova E, et al. Interferon-b and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell based assays. *J Gen Virol* 2014;95:571-577. Download the PDF from: http://vir.sgmjournals.org/content/95/Pt_3/571.full.pdf

3. Chan JF, Chan KH, Kao RY, To KK, Zheng BJ, Li CP, Li PT, Dai J, Mok FK, Chen H, Hayden FG, Yuen KY. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. *J Infect* 2013;67(6):606-16. Download the PDF from: http://www.journalofinfection.com/article/S0163-4453(13)00298-3/pdf

4. Chan JFW, Yao Y, Yeung M-L, et al. Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a non-human primate model of common marmoset. *J Infect Dis* 2015;212(12):1904-1. Download the PDF from: http://jid.oxfordjournals.org/content/early/2015/07/20/infdis.jiv392.short

5. AlGhamdi M, Mushtaq F, Awn N, Shalhoub S. MERS CoV infection in two renal transplant recipients: case report. *Am J Transplant* 2015;15:1101-4. Download the PDF from: https://www.ncbi.nlm.nih.gov/pubmed/25716741

6. Faure E, Poissy J, Goffard A, et al. Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside? *PLoS One* 2014; 9:e88716. Download the PDF from: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088716

**R. Nitazoxinide**

1. Haffizulla J, Hartman A, Hoppers M et al. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza – a double blind, randomised, placebo-controlled phase Information for Clinicians. Clinical decision-making support for treatment of MERS-CoV patients.

2b/3 trial. Rossignol JF, Samudrala S, Hoppers M. *Lancet infect Dis* 2014. Download the PDF from: [http://www.sciencedirect.com/science/article/pii/S1473309914707170](http://www.sciencedirect.com/science/article/pii/S1473309914707170)

2. Belardo G, La Frazia S, Cenciarelli O. Nitazoxanide, a Novel Potential Anti-Influenza Drug, Acting in Synergism with Neuraminidase Inhibitors. IDSA: Boston, 2011. Download the PDF from: [https://idsa.confex.com/idsa/2011/webprogram/Paper31075.html](https://idsa.confex.com/idsa/2011/webprogram/Paper31075.html)

3. Cao J, Forrest JC, Zhang X. A screen of the NIH Clinical Collection small molecule library identifies potential anti-coronavirus drugs. *Antiviral Res* 2015;114:1-10. Download the PDF from: [http://linkinghub.elsevier.com/retrieve/pii/S01663542(14)00331-3](<http://linkinghub.elsevier.com/retrieve/pii/S01663542(14)00331-3>)

4. Rossignol JF. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. *J Infect Public Health* 2016; 9,227—230 Download the PDF from: [http://www.jiph.org/article/S1876-0341(16)30018-1/pdf](<http://www.jiph.org/article/S1876-0341(16)30018-1/pdf>)

S. Protease inhibitors

1. Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. *Thorax* 2004;59(3):252-6. Download the PDF from: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1746980/pdf/v059p00252.pdf](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1746980/pdf/v059p00252.pdf)

2. Chan KS, Lai ST, Chu CM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicenter retrospective matched cohort study. *Hong Kong Med J* 2003;9: 399–406. Download the PDF from: [http://www.hkmj.org/article_pdfs/hkm0312p399.pdf](http://www.hkmj.org/article_pdfs/hkm0312p399.pdf)

3. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. *PLoS Med* 2006;3(9):e343. Download the PDF from: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1564166/pdf/pmed.0030343.pdf](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1564166/pdf/pmed.0030343.pdf)

4. Wong SSY, Yuen KY. The management of coronavirus infections with particular reference to SARS. *J Antimicrob Chemother* 2008;62(3):437-41. Download the PDF from: [http://jac.oxfordjournals.org/content/62/3/437.full.pdf+html](http://jac.oxfordjournals.org/content/62/3/437.full.pdf+html)

5. Barnard DL, Kumaki Y. Recent developments in anti-severe acute respiratory syndrome coronavirus chemotherapy. *Future Virol* 2011;6(5):615-31. Download the PDF from: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136164/pdf/nihms304163.pdf](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136164/pdf/nihms304163.pdf)

6. de Wilde AH, Jochmans D, Posthuma CC et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. *Antimicrob Agents Chemother* 2014; 58(8):4875-84. Download the PDF from: [http://aac.asm.org/content/early/2014/05/13/AAC.03011-14.full.pdf+html](http://aac.asm.org/content/early/2014/05/13/AAC.03011-14.full.pdf+html)

7. Chan JFW, Yao Y, Yeung M-L, et al. Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a non-human primate model of common marmoset. *J Infect Dis* 2015;212(12):1904-13. Download the PDF from: Information for Clinicians. Clinical decision-making support for treatment of MERS-CoV patients.

http://jid.oxfordjournals.org/content/early/2015/07/20/infdis.jiv392.short

8. Spanakis N, Tsiodras S, Haagmans BL, et al. Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen. *Int J Antimicrob Agents* 2014;44(6):528-32. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S0924857914002787#

9. Choi WS, Kang C-I, Kim Y, et al. Clinical Presentation and Outcomes of Middle East Respiratory Syndrome in the Republic of Korea. *Infect Chemother* 2016;48(2):118-126. Download the PDF from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945721/pdf/ic-48-118.pdf

**T. Ribavirin**

1. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. *PLoS Med* 2006;3(9):e343. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1564166/pdf/pmed.0030343.pdf

2. Morgenstern B, Michaelis M, Baer PC, Doerr HW, Cinatl J Jr. Ribavirin and interferon-beta synergistically inhibit SARS-associated coronavirus replication in animal and human cell lines. *Biochem Biophys Res Commun* 2005;326(4):905-8. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S0006291X04027299

3. Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ, Feldmann H. Inhibition of novel human coronavirus-EMC replication by a combination of interferon-a2b and ribavirin. *Sci Rep* 2013; 3:1686. Download the PDF from: http://www.biomedsearch.com/attachments/00/23/59/49/23594967/srep01686.pdf

4. Falzarano D, de Wit E, Rasmussen AL, et al. Treatment with interferon-a2b and ribavirin improves outcome in MERS-CoV–infected rhesus macaques. *Nat Med* 2013;19(10):1313-7. Download the PDF from: http://dx.doi.org/10.1038/nm.3362

5. Al-Tawfiq JA, Mommatin H, Dib J, Memish ZA. Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. *Int J Infect Dis* 2014;20:42-6. Download the PDF from: http://dx.doi.org/10.1016/j.ijid.2013.12.003

6. Khalid M, Khan B, Al Rabiah F, et al. Middle Eastern Respiratory Syndrome Corona Virus (MERS CoV): case reports from a tertiary care hospital in Saudi Arabia. *Ann Saudi Med* 2014;34(5):396-400. Download the PDF from: http://www.annsaudimed.net/files.php?force&file=2014_0435_OA_233141539.pdf

7. Khalid M, Al Rabiah F, Khan B, Al Mobeireek A, Butt TS, Al Mutairy E. Ribavirin and interferon-a2b as primary and preventive treatment for Middle East respiratory syndrome coronavirus: a preliminary report of two cases. *Antivir Ther* 2015;20:87-91. Download the PDF from: http://www.intmedpress.com/journals/avt/abstract.cfm?id=2792&pid=48

8. Shalhoub S, Farahat F, Al-Jiffri A, Simhairi R, Shamma O, Siddiqi N, Mushtaq A. IFN-a2a Information for Clinicians. Clinical decision-making support for treatment of MERS-CoV patients.

or IFN-β1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. *J Antimicrob Chemother* 2015;70(7):2129-32. Download the PDF from: [http://jac.oxfordjournals.org/content/70/7/2129.full.pdf+html](http://jac.oxfordjournals.org/content/70/7/2129.full.pdf+html)

09. Spanakis N, Tsiodras S, Haagmans BL, et al. Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen. *Int J Antimicrob Agents* 2014;44(6):528-32. Download the PDF from: [http://www.sciencedirect.com/science/article/pii/S0924857914002787](http://www.sciencedirect.com/science/article/pii/S0924857914002787)

10. Omrani AS, Saad MM, Baig K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. *Lancet Infect Dis* 2014;14(11):1090-5. Download the PDF from: [http://linkinghub.elsevier.com/retrieve/pii/S147330991400920X](http://linkinghub.elsevier.com/retrieve/pii/S147330991400920X)

11. Hart BJ, Dyall J, Postnikova E, et al. Interferon-b and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell based assays. *J Gen Virol* 2014;95:571-577. Download the PDF from: [http://vir.sgmjournals.org/content/95/Pt_3/571.full.pdf+html?sid=b01f8c80-bde3-49d9-b716-c9b153f5dddc](http://vir.sgmjournals.org/content/95/Pt_3/571.full.pdf+html?sid=b01f8c80-bde3-49d9-b716-c9b153f5dddc)

12. van Vonderen MGA, Bos JC, Prins JM, Wertheim-van Dillen P, Speelman P. Ribavirin in the treatment of severe acute respiratory syndrome (SARS). *Neth J Med* 2003;61(7):238-41. Download the PDF from: [http://www.njmonline.nl/getpdf.php?id=25](http://www.njmonline.nl/getpdf.php?id=25)

13. Sung JJ, Wu A, Joynt GM, et al. Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak. *Thorax* 2004;59(5):414-20. Download the PDF from: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1746995/pdf/v059p00414.pdf](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1746995/pdf/v059p00414.pdf)

14. Chan JF, Chan KH, Kao RY, et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. *J Infect* 2013;67(6):606-16. Download the PDF from: [http://www.journalofinfection.com/article/S01634453(13)002983/pdf](<http://www.journalofinfection.com/article/S01634453(13)002983/pdf>)

15. Adedeji AO, Sarafianos SG. Future treatment strategies for novel Middle East respiratory syndrome coronavirus infection. *Future Med Chem* 2013;5(18):2119–2122. Download the PDF from: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085789/pdf/nihms606665.pdf](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085789/pdf/nihms606665.pdf)

16. Gross AE, Bryson ML. Oral Ribavirin for the Treatment of Noninfluenza Respiratory Viral Infections: A Systematic Review. *Ann Pharmacother* 2015;49(10):1125-35. Download the PDF from: [http://journals.sagepub.com/doi/pdf/10.1177/1060028015597449](http://journals.sagepub.com/doi/pdf/10.1177/1060028015597449)

17. Al Ghamdi M, Al Ghamdi M, Ghandoor Y, et al. Treatment outcomes for patients with Middle Eastern Respiratory Syndrome Coronavirus (MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia. *BMC Infect Dis* 2016;16:174. Download PDF from: [https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-016-1492-4](https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-016-1492-4)

18. Arabi YM, Shalhoub S, Al Omari A, et al. Effect of ribavirin and interferon on the outcome Information for Clinicians. Clinical decision-making support for treatment of MERS-CoV patients.

of critically ill patients with MERS. ATS: Washington, 2017. Abstract 9690. Abstract available from: http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2017.195.1_MeetingAbstracts.A6067

U. SiRNA

1. Li BJ, Tang Q, Cheng D, et al. Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque. *Nat Med* 2005;11(9):944-51. Download the PDF from: http://www.nature.com/nm/journal/v11/n9/pdf/nm1280.pdf

2. Haagmans BL, Osterhaus ADME. Coronaviruses and their therapy. *Antivir Res* 2006;71(2-3 Spec. Iss.):397-403. Download the PDF from: http://www.sciencedirect.com/science/article/pii/S0166354206001707

V. Vaccine

1. Tang J, Zhang N, Tao X, et al. Optimization of antigen dose for a receptor-binding domain-based subunit vaccine against MERS coronavirus. *Hum Vaccin Immunother* 2015;11(15):1244-50. Download the PDF from: http://www.tandfonline.com/doi/abs/10.1080/21645515.2015.1021527?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed

2. Muthumani K, Falzarano D, Reuschel EL, et al. A synthetic consensus anti-spike protein DNA vaccine induces protective immunity against Middle East respiratory syndrome coronavirus in nonhuman primates. *Sci Transl Med* 2015;7(301):301ra132. Download the PDF from: http://stm.sciencemag.org/cgi/pmidlookup?view=short&pmid=26290414

W. Viral loads

1. Hung IF, Cheng VC, Wu AK, et al. Viral loads in clinical specimens and SARS manifestations. *Emerg Infect Dis* 2004;10(9):1550-7. Download the PDF from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320271/pdf/04-0058.pdf

2. Oh MD, Park WB, Choe PG et al. Viral Load Kinetics of MERS Coronavirus Infection. *N Engl J Med* 2016;375(13):1303-5. Download the PDF from: https://www.ncbi.nlm.nih.gov/pubmed/27682053

3. Corman VM, Albarrak AM, Omrani AS et al. Viral Shedding and Antibody Response in 37 Patients With Middle East Respiratory Syndrome Coronavirus Infection. *Clin Infect Dis* 2016;62(4):47783. Download the PDF from: https://www.ncbi.nlm.nih.gov/pubmed/26565003